Liquid dosage forms of sodium naproxen

ABSTRACT

Described herein are oral pharmaceutical compositions comprising liquid dosage forms of sodium naproxen in soft gel capsules. In one embodiment, the pharmaceutical composition comprises sodium naproxen, 0.2-1.0 mole equivalents of a de-ionizing agent per mole of naproxen, polyethylene glycol, and one or more solubilizers such as propylene glycol, polyvinyl pyrrolidone or a combination thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/591,512, filed on May 10, 2017, which is a continuation of U.S.patent application Ser. No. 14/977,808, filed on Dec. 22, 2015, now U.S.Pat. No. 9,693,978, which is continuation of U.S. patent applicationSer. No. 11/367,238, filed Mar. 3, 2006, now abandoned, which claimspriority under 35 U.S.C. § 119(e) to U.S. Provisional Patent ApplicationNo. 60/659,679, filed Mar. 8, 2005, each of which is incorporated hereinin its entirety by express reference thereto.

TECHNICAL FIELD

This application describes liquid dosage forms of sodium naproxen insoft gelatin capsules.

BACKGROUND

Filled one-piece soft gelatin capsules (“softgels”) have been widelyused for years to encapsulate consumable materials such as vitamins andpharmaceuticals in a liquid vehicle or carrier. Because softgels haveproperties which are quite different from two-piece hardshell capsules,softgels are more capable of retaining a liquid fill material.

Not all liquids may be enclosed in a softgel capsule. Liquids containingmore than about 20% water by weight are generally not enclosed insoftgels, because the water tends to dissolve the gelatin shell. Othersolvents such as propylene glycol, glycerin, low molecular weightalcohols, ketones, acids, amines, and esters all tend to degrade ordissolve the gelatin shell to some extent.

Softgels are also somewhat sensitive to pH, and generally require a pHin the encapsulated liquid from about 2.5 to about 7.5. Highly acidicliquids may hydrolyze the gelatin, resulting in leaks, while basicliquids may tan the gelatin, resulting in decreased solubility of thegelatin shell.

Pharmaceutical liquids are usually enclosed in softgels as eitherviscous solutions or suspensions. Suspensions are pharmaceutically lessdesirable because they can settle during manufacture, which leads to aless uniform product. In contrast, solutions provide the best liquidform for obtaining optimal “content uniformity” in a batch. Further,solutions typically provide a faster and more uniform absorption of anactive agent than do suspensions.

Suitable softgel solutions, however, can be difficult to achieve. Oneconstraint is size. Many pharmaceutical agents require volumes ofsolvent too large to produce a softgel capsule small enough to be takenby patients. The solvent must also have sufficient solvating power todissolve a large amount of the pharmaceutical agent to produce aconcentrated solution and yet not dissolve, hydrolyze or tan the gelatinshell.

Concentrated solutions of pharmaceutical agents for use in softgelcapsules have been described. Most of these systems involve ionizing thefree pharmaceutical agent in situ to the corresponding salt. Forexample, U.S. Pat. No. 5,360,615 to Yu et al. discloses a solvent systemfor enhancing the solubility of acidic, basic, or amphotericpharmaceutical agents. The solvent system comprises polyethylene glycol,an ionizing agent, and water. The ionizing agent functions by causingthe partial ionization of the free pharmaceutical agent. U.S. Pat. No.6,383,515, U.S. Patent Application Publication No. 2002/0187195, andU.S. Patent Application Publication No. 2001/0007668 to Sawyer et al.discloses pharmaceutically acceptable solutions containing a medicamentsuitable for filling softgel capsules comprising a polymer such aspolyethylene glycol and an acid salt of a compound having three or morecarbon atoms, such as sodium propionate. The salt helps to ionize themedicament without relying on the use of strong acids or bases. U.S.Pat. No. 6,689,382 to Berthel et al. describes a pharmaceuticalformulation suitable for filling softgel capsules comprising (a) atherapeutically effective amount of a non-steroidal anti-inflammatorydrug (NSAID); and (b) a solvent system comprising 40% to 60% by weight apolyoxyethylene ether, 15% to 35% by weight of glycerin and 15% to 35%by weight water. In cases where the NSAID has a carboxyl or an acidicfunctional group, the solvent system also includes hydroxide ions. U.S.Pat. No. 5,505,961 to Shelley et al. describes a method for increasingthe solubility of acetaminophen alone or in combination with otherpharmaceutically active agents to form a clear solution forencapsulation into a softgel capsule. The method comprises solubilizingacetaminophen in a mixture of propylene glycol, polyethylene glycol,water, polyvinylpyrrolidone and sodium or potassium acetate.

The previously described methods all involve the conversion of the freepharmaceutical agent to the corresponding salt. In cases where the freepharmaceutical agent is acidic, the resulting anion can react with thepolyethylene glycol in the fill to produce polyethylene glycol esters,thus reducing the amount of available pharmaceutical agent.

There is a need for a solvent system containing a medicament, which canbe encapsulated in a softgel capsule, wherein the formation of PEGesters is minimized.

Therefore, it is an object of the invention to provide a stable solventsystem for pharmaceutical agents, which is suitable for encapsulation ina softgel capsule, wherein the formation of PEG esters is minimized.

SUMMARY

Liquid and semi-solid pharmaceutical compositions, which can beadministered in liquid form or can be used for preparing capsules, aredescribed herein. The composition comprises the salt of one or moreactive agents, such as naproxen, and 0.2-1.0 mole equivalents of ade-ionizing agent per mole of active agent. The pH of the composition isadjusted within the range of 2.5-7.5. The de-ionizing agent causespartial de-ionization (neutralization) of the salt of the active agentresulting in enhanced bioavailability of salts of weakly acidic, basicor amphoteric active agents as well as decreased amounts of polyethyleneglycol (PEG) esters.

Described herein are oral pharmaceutical compositions comprising liquiddosage forms of sodium naproxen in soft gel capsules. In one embodiment,the pharmaceutical composition comprises sodium naproxen, 0.2-1.0 moleequivalents of a de-ionizing agent per mole of naproxen, polyethyleneglycol, and one or more solubilizers such as propylene glycol, polyvinylpyrrolidone or a combination thereof.

One embodiment described herein is a pharmaceutical compositioncomprising a soft gel capsule encapsulating a liquid matrix comprising:(a) naproxen sodium; (b) one or more deionizing agents comprisingfumaric acid, maleic acid, tartaric acid, citric acid, malic acid,acetic acid, proprionic acid, pyruvic acid, butanoic acid, or lacticacid in an amount of from 0.2 to 1.0 mole equivalents per mole ofnaproxen sodium; (c) one or more polyethylene glycols; and (d) one ormore solubilizers comprising polyvinylpyrrolidone, propylene glycol, ora combination thereof. In one aspect described herein, the deionizingagent comprises citric acid or lactic acid. In another aspect describedherein, the deionizing agent comprises lactic acid. In another aspectdescribed herein, the polyethylene glycol comprises from about 10% toabout 80% by weight of the composition. In another aspect describedherein, the polyethylene glycol comprises one or more polyethyleneglycols with a molecular weight between 300 and 1500. In another aspectdescribed herein, the polyethylene glycol comprises polyethylene glycol600. In another aspect described herein, the solubilizer comprises fromabout 1% to 10% by weight of the composition. In another aspectdescribed herein, the solubilizer comprises about 2%polyvinylpyrrolidone and about 2% propylene glycol. In another aspectdescribed herein, the composition further comprises one or moreexcipients comprising plasticizers, crystallization inhibitors, wettingagents, bulk filling agents, solubilizers, bioavailability enhancers,solvents, dyes, preservatives, surfactants, or combinations thereof.

Another embodiment described herein is a pharmaceutical compositioncomprising: (a) about 25% naproxen sodium by weight; (b) lactic acid inan amount of from about 0.2 to about 1.0 mole equivalents per mole ofnaproxen sodium; (c) about 10% to about 80% of one or more polyethyleneglycols by weight; and (d) about 1% to about 10% by weight of one ormore solubilizers comprising polyvinylpyrrolidone, propylene glycol, ora combination thereof. In one aspect described herein, the polyethyleneglycol comprises one or more polyethylene glycols with a molecularweight between 300 and 1500. In another aspect described herein, thepolyethylene glycol comprises polyethylene glycol 600. In another aspectdescribed herein, the solubilizer comprises propylene glycol andpolyvinyl pyrrolidone. In another aspect described herein, the lacticacid comprises about 0.6 mole equivalents per mole of naproxen sodium.In another aspect described herein, the weight percentage of lactic acidis about 5%. In another aspect described herein, the solubilizercomprises about 2% polyvinylpyrrolidone and about 2% propylene glycol.In another aspect described herein, the composition further comprisesone or more excipients selected from plasticizers, crystallizationinhibitors, wetting agents, bulk filling agents, bioavailabilityenhancers, solvents, dyes, preservatives, surfactants, or combinationsthereof. In another aspect described herein, the pH is from about 2.5 toabout 7.5. In another aspect described herein, the composition isencapsulated in a softgel capsule. In another aspect described herein,the softgel capsule comprises: (a) gelatin; (b) plasticizer; and (c)purified water.

Another embodiment described herein is a method for making apharmaceutical composition, the method comprising: (a) mixing together(i) about 25% naproxen sodium by weight; (ii) lactic acid in an amountof from about 0.2 to about 1.0 mole equivalents per mole of naproxensodium; (ii) about 10% to about 80% of one or more polyethylene glycolsby weight; and (iv) about 1% to about 10% by weight of one or moresolubilizers comprising polyvinylpyrrolidone, propylene glycol, or acombination thereof; and (b) encapsulating the mixture in a softgelcapsule using rotary die encapsulation.

Another embodiment described herein is an oral dosage form produced bythe method described herein.

DETAILED DESCRIPTION I. Composition

A. Fill Materials

1. Drugs to be Formulated

The formulation can contain any therapeutic, diagnostic, prophylactic ornutraceutical agent. Exemplary agents include, but are not limited to,analeptic agents; analgesic agents; anesthetic agents; antiasthmaticagents; antiarthritic agents; anticancer agents; anticholinergic agents;anticonvulsant agents; antidepressant agents; antidiabetic agents;antidiarrheal agents; antiemetic agents; antihelminthic agents;antihistamines; antihyperlipidemic agents; antihypertensive agents;anti-infective agents; anti-inflammatory agents; antimigraine agents;antineoplastic agents; antiparkinson drugs; antipruritic agents;antipsychotic agents; antipyretic agents; antispasmodic agents;antitubercular agents; antiulcer agents; antiviral agents; anxiolyticagents; appetite suppressants (anorexic agents); attention deficitdisorder and attention deficit hyperactivity disorder drugs;cardiovascular agents including calcium channel blockers, antianginalagents, central nervous system (“CNS”) agents, beta-blockers andantiarrhythmic agents; central nervous system stimulants; diuretics;genetic materials; hormonolytics; hypnotics; hypoglycemic agents;immunosuppressive agents; muscle relaxants; narcotic antagonists;nicotine; nutritional agents; parasympatholytics; peptide drugs;psychostimulants; sedatives; sialagogues, steroids; smoking cessationagents; sympathomimetics; tranquilizers; vasodilators; beta-agonist; andtocolytic agents.

A first class of drugs is selected based on inclusion in the molecule ofa weakly acidic, basic or amphoteric group that can form a salt. Anydrug that bears an acidic or a basic functional group, for example, anamine, imine, imidazoyl, guanidine, piperidinyl, pyridinyl, quaternaryammonium, or other basic group, or a carboxylic, phosphoric, phenolic,sulfuric, sulfonic or other acidic group, can react with the de-ionizingagent.

Some specific drugs that bear acidic or basic functional groups and thusmay be converted to the corresponding salt for use in the describedformulations include, but are not limited to, Acetaminophen,Acetylsalicylic acid, Alendronic acid, Alosetron, Amantadine,Amlopidine, Anagrelide, Argatroban, Atomoxetine, Atrovastatin,Azithromycin dehydrate, Balsalazide, Bromocriptan, Bupropion,Candesartan, Carboplatin, Ceftriaxone, Clavulonic acid, Clindamycin,Cimetadine, Dehydrocholic (acid), Dexmethylphenidate, Diclofenac,Dicyclomine, Diflunisal, Diltiazem, Donepezil, Doxorubicin, Doxepin,Epirubicin, Etodolic acid, Ethacrynic acid, Fenoprofen, Fluoxetine,Flurbiprofen, Furosemide, Gemfibrozil, Hydroxyzine, Ibuprofen,Imipramine, Indomethacin, Ketoprofen, Levothyroxine, Maprolitline,Meclizine, Methadone, Methylphenidate, Minocycline, Mitoxantone,Moxifloxacin, Mycophenolic acid, Naproxen, Niflumic acid, Ofloxacin,Ondansetron, Pantoprazole, Paroxetine, Pergolide, Pramipexole,Phenytoin, Pravastain, Probenecid, Rabeprazole, Risedronic acid,Retinoic acid, Ropinirole, Selegiline, Sulindac, Tamsulosin,Telmisertan, Terbinafine, Theophyline, Tiludronic Acid, Tinzaparin,Ticarcillin, Tometin, Valproic acid, Salicylic acid, Sevelamer,Ziprasidone, Zoledronic acid, Acetophenazine, Albuterol, Almotriptan,Amitriptyline, Amphetamine, Atracurium, Beclomethasone, Benztropine,Biperiden, Bosentan, Bromodiphenhydramine, Brompheniraminecarbinoxamine, Caffeine, Capecitabine, Carbergoline, Cetirizine,Chlocylizine, Chlorpheniramine, Chlorphenoxamine, Chlorpromazine,Citalopram, Clavunate potassium, Ciprofloxacin, Clemastine, Clomiphene,Clonidine, Clopidogrel, Codeine, Cyclizine, Cyclobenzaprine,Cyproheptadine, Delavirdine, Diethylpropion, Divalproex, Desipramine,Dexmethylphenidate, Dexbrompheniramine, Dexchlopheniramine, Dexchlor,Dextroamphetamine, Dexedrine, Dextromethorphan, Fiflunisal, Diphemanilmethylsulphate, Diphenhydramine, Dolasetron, Doxylamine, Enoxaparin,Ergotamine, Ertepenem, Eprosartan, Escitalopram, Esomeprazole,Fenoldopam, Fentanyl, Fexofenadine, Flufenamic acid, Fluvastatin,Fluphenazine, Fluticasone, Fosinopril, Frovatriptan, Gabapentin,Galatamine, Gatifloxacin, Gemcitabine, Haloperidol, Hyalurondate,Hydrocodone, Hydroxychloroquine, Hyoscyamine, Imatinib, Imipenem,Ipatropin, Lisinopril, Leuprolide, Levopropoxyphene, Losartan,Meclofenamic acid, Mefanamic acid, Mesalamine, Mepenzolate, Meperidine,Mephentermine, Mesalimine, Mesoridazine, Metaproteranol, Metformin,Methdialazine, Methscopolamine, Methysergide, Metoprolol, Metronidazole,Mibefradil, Montelukast, Morphine, Mometasone, Naratriptan, Nelfinavir,Nortriptylene, Noscapine, Nylindrin, Omeprazole, Orphenadrine,Oseltamivir, Oxybutynin, Papaverine, Pentazocine, Phendimetrazine,Phentermine, Pioglitazone, Pilocarpine, Prochloroperazine, Pyrilamine,Quetapine, Ranitidine, Rivastigmine, Rosiglitazone, Salmetrol,Sertaline, Sotalol, Sumatriptan, Tazobactam, Tacrolimus, Tamoxifen,Ticlopidine, Topiramate, Tolterodine, Triptorelin, Triplennamine,Triprolidine, Tramadol, Trovofloxacin, Ursodiol, Promazine,Propoxyphene, Propanolol, Pseudoephedrine, Pyrilamine, Quinidine,Oxybate sodium, Sermorelin, Tacrolimus, Tegaseroid, Teriparatide,Tolterodine, Triptorelin pamoate, Scoplolamine, Venlafaxine, Zamivir,Aminocaproic acid, Aminosalicylic acid, Hydromorphone, Isosuprine,Levorphanol, Melhalan, Nalidixic acid, and Para-aminosalicylic acid.

2. Deionizing Agent

The deionizing agent functions by causing partial deionization(neutralization) of the salt of one or more pharmaceutically activeagents. When the active agent is the salt of a weak acid and a strongbase, the deionizing agent is preferably a hydrogen ion species. Whenthe active agent is the salt of a weak base and a strong acid, thedeionizing agent is preferably a hydroxide ion species. The deionizingagent is preferably present in an amount between 0.2 to 1.0 moleequivalents per mole of the pharmaceutically active agent.

Exemplary hydrogen ion species useful as de-ionizing agents describedherein, include, but are not limited to, hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfuric acid, fumaric acid, maleic acid,tartaric acid, methane-, ethane-, and benzene sulfonates, citric acid,malic acid, acetic acid, proprionic acid, pyruvic acid, butanoic acid,and lactic acid.

Exemplary hydroxide ion species useful as de-ionizing agents describedherein, include, but are not limited to, metal hydroxides such as sodiumhydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide,aluminum hydroxide, and magnesium hydroxide.

Additional acid or base can be added to adjust the pH of the fillcomposition. In a preferred embodiment, the pH of the fill compositionis from about 2.5 to about 7.5.

3. Excipients

Formulations may be prepared using a pharmaceutically acceptable carriercomposed of materials that are considered safe and effective and may beadministered to an individual without causing undesirable biologicalside effects or unwanted interactions. The carrier is all componentspresent in the pharmaceutical formulation other than the activeingredient or ingredients. As generally used herein “carrier” includes,but is not limited to, plasticizers, crystallization inhibitors, wettingagents, bulk filling agents, solubilizers, bioavailability enhancers,solvents, pH-adjusting agents and combinations thereof.

In a preferred embodiment, a mixture of polyethylene glycol and water isused as a solvent for the salt of the active agent and the de-ionizingagent. Polyethylene glycol is present in an amount from about 10% toabout 80% by weight. Water is present in an amount from about 1% to 18%by weight. The molecular weight of polyethylene glycol is between 300and 1500. Other suitable solvents include surfactants and copolymers ofpolyethylene glycol. Optionally, glycerin, polyvinyl pyrrolidone (PVP)or propylene glycol (PPG) can be added to enhance the solubility of thedrug agent.

B. Shell Compositions

1. Gelatin

Gelatin is the product of the partial hydrolysis of collagen. Gelatin isclassified as either Type A or Type B gelatin. Type A gelatin is derivedfrom the acid hydrolysis of collagen while Type B gelatin is derivedfrom alkaline hydrolysis of collagen. Traditionally, bovine bones andskins have been used as raw materials for manufacturing Type A and TypeB gelatin while porcine skins have been used extensively formanufacturing Type A gelatin. In general acid-processed gelatins formstronger gels than lime-processed gelatins of the same average molecularweight.

2. Other Shell Additives

Other suitable shell additives include plasticizers, opacifiers,colorants, humectants, preservatives, flavorings, and buffering saltsand acids.

Plasticizers are chemical agents added to gelatin to make the materialsofter and more flexible. Suitable plasticizers include glycerin,sorbitol solutions which are mixtures of sorbitol and sorbitan, andother polyhydric alcohols such as propylene glycol and maltitol orcombinations thereof.

Opacifiers are used to opacify the capsule shell when the encapsulatedactive agents are light sensitive. Suitable opacifiers include titaniumdioxide, zinc oxide, calcium carbonate and combinations thereof.

Colorants can be used to for marketing and productidentification/differentiation purposes. Suitable colorants includesynthetic and natural dyes and combinations thereof.

Humectants can be used to suppress the water activity of the softgel.Suitable humectants include glycerin and sorbitol, which are oftencomponents of the plasticizer composition. Due to the low water activityof dried, properly stored softgels, the greatest risk frommicroorganisms comes from molds and yeasts. For this reason,preservatives can be incorporated into the capsule shell. Suitablepreservatives include alkyl esters of p-hydroxy benzoic acid such asmethyl, ethyl, propyl, butyl and heptyl (collectively known as“parabens”) or combinations thereof.

Flavorings can be used to mask unpleasant odors and tastes of fillformulations. Suitable flavorings include synthetic and naturalflavorings. The use of flavorings can be problematic due to the presenceof aldehydes which can cross-link gelatin. As a result, buffering saltsand acids can be used in conjunction with flavorings that containaldehydes in order to inhibit cross-linking of the gelatin.

II. Methods of Making

A. Fill Material

The fill material is prepared by mixing the agent (such as a salt of thedrug), the deionizing agent, water, and polyethylene glycol at atemperature of 50° C. to 70° C. The resulting solution is encapsulatedusing the appropriate gel mass. The pharmaceutical agent is present inan amount from about 10% to about 50% by weight. The deionizing agent ispresent in an amount from about 0.2 to 1.0 mole per mole of thepharmaceutical agent. Water is present in an amount from about 1% toabout 20% by weight and polyethylene glycol is present in amount fromabout 10% to about 80% by weight. Optionally, propylene glycol and/orpolyvinyl pyrrolidone are present in an amount from about 1% to about10%.

B. Gel Mass

The main ingredients of the softgel capsule shell are gelatin,plasticizer, and purified water. Typical gel formulations contain (w/w)40-50% gelatin, 20-30% plasticizer, and 30-40% purified water. Most ofthe water is subsequently lost during capsule drying. The ingredientsare combined to form a molten gelatin mass using either a cold melt or ahot melt process. The prepared gel masses are transferred to preheated,temperature-controlled, jacketed holding tanks where the gel mass isaged at 50-60° C. until used for encapsulation.

1. Cold Melt Process

The cold melt process involves mixing gelatin with plasticizer andchilled water and then transferring the mixture to a jacket-heated tank.Typically, gelatin is added to the plasticizer at ambient temperature(18-22° C.). The mixture is cooked (57-95° C.) under vacuum for 15-30minutes to a homogeneous, deaerated gel mass. Additional shell additivescan be added to the gel mass at any point during the gel manufacturingprocess or they may be incorporated into the finished gel mass using ahigh torque mixer.

2. Hot Melt Process

The hot melt process involves adding, under mild agitation, the gelatinto a preheated (60-80° C.) mixture of plasticizer and water and stirringthe blend until complete melting is achieved. While the hot melt processis faster than the cold melt process, it is less accurately controlledand more susceptible to foaming and dusting.

C. Softgel Capsule

Softgel capsules are typically produced using a rotary die encapsulationprocess. The gel mass is fed either by gravity or through positivedisplacement pumping to two heated (48-65° C.) metering devices. Themetering devices control the flow of gel into cooled (10-18° C.),rotating casting drums. Ribbons are formed as the cast gel masses set oncontact with the surface of the drums.

The ribbons are fed through a series of guide rolls and betweeninjection wedges and the capsule-forming dies. A food-grade lubricantoil is applied onto the ribbons to reduce their tackiness and facilitatetheir transfer. Suitable lubricants include mineral oil, medium chaintriglycerides, and soybean oil. Fill formulations are fed into theencapsulation machine by gravity. In the preferred embodiment, thesoftgels contain printing on the surface, optionally identifying theencapsulated agent and/or dosage.

III. Methods of Use

The softgels may be used to encapsulate a wide range of pharmaceuticallyactive agents, nutritional agents, and personal care products. Softgelcapsules may be administered orally to a patient to deliver apharmaceutically active agent.

It is understood that the disclosed invention is not limited to theparticular methodology, protocols, and reagents described as these mayvary. It is also to be understood that the terminology used herein isfor the purpose of describing particular embodiments only, and is notintended to limit the scope of the present invention which will belimited only by the appended claims.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of skill in the artto which the disclosed invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methods,devices, and materials are as described. Publications cited herein andthe materials for which they are cited are specifically incorporated byreference. Nothing herein is to be construed as an admission that theinvention is not entitled to antedate such disclosure by virtue of priorinvention.

Examples

In the following examples, the fill material can be prepared by mixingthe salt of one or more pharmaceutically active agents, the deionizingagent, water, and polyethylene glycol at a temperature of 50° C. to 70°C. The resulting solution can be encapsulated in a softgel capsule usingthe appropriate gel mass.

Example 1. Naproxen Sodium with Acetic Acid as the Deionizing Agent FillMaterial Ingredients % (by weight) Naproxen Sodium 25.50 Acetic Acid3.00 PVP 1.85 PEG 400 62.30 Water 7.40 TOTAL 100%

Example 2. Naproxen Sodium with Citric Acid as the Deionizing Agent FillMaterial Ingredients % (by weight) Naproxen Sodium 25.50 Citric Acid4.75 PVP 1.85 PEG 400 60.50 Water 7.40 TOTAL 100%

Example 3 Naproxen Sodium with Hydrochloric Acid as the Deionizing AgentFill Material Ingredients % (by weight) Naproxen Sodium 25.50Hydrochloric Acid 4.72 PVP 1.85 PEG 400 63.52 Water 7.40 TOTAL 100%

Example 4. Naproxen Sodium with Acetic Acid as the Deionizing Agent FillMaterial Ingredients % (by weight) Naproxen Sodium 25.50 Acetic Acid3.00 PVP 1.85 PEG 400 31.15 Water 7.40 PEG 600 31.15 TOTAL 100%

Example 5. Naproxen Sodium with Citric Acid as the Deionizing Agent FillMaterial Ingredients % (by weight) Naproxen Sodium 25.50 Citric Acid40.75 PVP 1.85 PEG 400 30.25 Water 7.40 PEG 600 30.25 TOTAL 100%

Example 6. Naproxen Sodium with Hydrochloric Acid as the DeionizingAgent Fill Material Ingredients % (by weight) Naproxen Sodium 25.50Hydrochloric Acid 40.72 PVP 1.85 PEG 400 30.25 Water 7.40 PEG 600 30.25TOTAL 100%

Example 7. Naproxen Sodium with Lactic Acid as the Deionizing Agent FillMaterial Ingredients % (by weight) Naproxen Sodium 27.50 Lactic Acid5.27 Propylene Glycol 2.00 PEG 400 64.64 Water 0.60 TOTAL 100%

Example 8. Naproxen Sodium with Lactic Acid as the Deionizing Agent FillMaterial Ingredients % (by weight) Naproxen Sodium 25.00 Lactic Acid0.24-0.35M Propylene Glycol  2.00 PEG 600 q.s. TOTAL 100%

Example 9. Naproxen Sodium with Lactic Acid as the Deionizing Agent FillMaterial Ingredients % (by weight) Naproxen Sodium 25.00 Lactic Acid5.00 Propylene Glycol 2.00 PEG 600 61.20 PEG 1000 6.80 TOTAL 100%

Example 10. Naproxen Sodium with Lactic Acid as the Deionizing AgentFill Material Ingredients % (by weight) Naproxen Sodium 25.00 LacticAcid 5.00 Propylene Glycol 2.00 PEG 600 51.00 PEG 1000 17.00 TOTAL 100%

Example 11. Naproxen Sodium with Lactic Acid as the Deionizing AgentFill Material Ingredients % (by weight) Naproxen Sodium 25.00 LacticAcid 5.00 Propylene Glycol 2.00 PEG 600 34.00 PEG 1000 34.00 TOTAL 100%

Example 12. Naproxen Sodium with Lactic Acid as the Deionizing AgentFill Material Ingredients % (by weight) Naproxen Sodium 25.00 LacticAcid 5.00 Propylene Glycol 2.00 PEG 600 17.00 PEG 1000 51.00 TOTAL 100%

1. A soft gelatin capsule comprising a fill material comprising: (a) anaproxen salt; (b) a deionizing agent comprising lactic acid in anamount of from 0.2 to 1.0 mole equivalents per mole of naproxen salt;(c) polyethylene glycol; and (d) one or more solubilizers.
 2. Thecapsule of claim 1, wherein the naproxen salt is naproxen sodium.
 3. Thecapsule of claim 1, wherein the fill material further comprises water inan amount from 1% to 18% by weight.
 4. The capsule of claim 1, whereinpolyethylene glycol is present in an amount from 10% to 80% by weight.5. The capsule of claim 1, wherein the polyethylene glycol comprises oneor more polyethylene glycols with a molecular weight between 300 and1500.
 6. The capsule of claim 1, wherein the solubilizer is present inamount from 1% to 10% by weight.
 7. The capsule of claim 1, wherein theone or more solubilizers comprise glycerin, polyvinylpyrrolidone,propylene glycol, or combinations thereof.
 8. The capsule of claim 1,further comprising one or more excipients comprising plasticizers,crystallization inhibitors, wetting agents, bulk filling agents,bioavailability enhancers, solvents, dyes, preservatives, surfactants,or combinations thereof.
 9. The capsule of claim 1, wherein the fillmaterial is liquid.
 10. A method for treating pain, inflammation, orfever comprising administering the capsule of claim 1 to a patient inneed thereof.
 11. A method of making the capsule of claim 1 comprising(a) mixing components (a), (b), (c), and (d) as defined in claim 1; and(b) encapsulating the mixture in a softgel capsule.
 12. The method ofclaim 11, wherein step (a) is conducted at a temperature of from 50° C.to 70° C.
 13. A soft gelatin capsule comprising a fill materialcomprising: (a) naproxen sodium; (b) a deionizing agent comprisinglactic acid in an amount of from 0.2 to 1.0 mole equivalents per mole ofnaproxen sodium; (c) polyethylene glycol; and (d) a solubilizercomprising glycerin, polyvinylpyrrolidone, propylene glycol, orcombinations thereof.
 14. The capsule of claim 13, wherein polyethyleneglycol is present in an amount from 10% to 80% by weight.
 15. Thecapsule of claim 13, wherein the polyethylene glycol comprises one ormore polyethylene glycols with a molecular weight between 300 and 1500.16. The capsule of claim 13, wherein the fill material further compriseswater in an amount from 1% to 18% by weight.
 17. The capsule of claim13, further comprising one or more excipients comprising plasticizers,crystallization inhibitors, wetting agents, bulk filling agents,bioavailability enhancers, solvents, dyes, preservatives, surfactants,or combinations thereof.
 18. The capsule of claim 13, wherein thesolubilizer is present in amount from 1% to 10% by weight.
 19. Thecapsule of claim 13, wherein the fill material is liquid.
 20. A methodfor treating pain, inflammation, or fever comprising administering thecapsule of claim 13 to a patient in need thereof.